In this renewal of the program project Grant, we will continue to investigate neurodegenerative disorders on Guam, namely Parkinson-Dementia Complex (PDC), Amyotrophic Lateral Sclerosis (ALS) and late-life dementia. The unifying feature among these disorders is the pathological finding of neurofibrillary tangles. We hypothesize that interactions between aging, genetics and environment may determine which type of clinical phenotype results. We will use a multidisciplinary approach to determine rates of disease and risk factors, identify susceptibility genes and potential mechanisms of disease, investigate biochemical and radiological markers that may assist in early diagnosis and differential diagnosis, and carry out clinicopathological studies. There will be 3 cores: Administrative and Data core; Clinical core (on Guam and in San Diego), and: Neuropathology-Brain Bank core, in New York. There will be 4 research subprojects. Subproject by Galasko: 'Prevalence and incidence of dementia among elderly Chamorros' aims to measure the prevalence and incidence of PDC and dementia among Chamorros and assess risk factors. Subproject by Schellenberg: 'Genetic studies of ALS, PDC and Dementia on Guam' aims to perform genome-wide searches for genetic alterations associated with ALS and PDC, and to examine candidate genes for PDC and dementia. Subproject by Kaye: 'MRI of Neurodegenerative Disease among aging Chamorros' aims to carry out volumetric analyses of the hippocampus and other brain regions to identify markers of disease and assist in early diagnosis. Subproject by Lee: 'PHF-tau in neurodegenerative diseases of Guam' will assess oxidative markers related to brain lesions in ALS, PDC and dementia.